Highly sensitive blood-based biomarkers detection of beta-amyloid and phosphorylated-tau181 for Alzheimer's disease.

Background: Plasma biomarker has the potential to be the reliable and propagable approach in the early stage diagnosis of Alzheimer's disease (AD). However, conventional methods appear powerless in the detection of these biomarkers at low concentrations in plasma. Here, we determined plasma biomarker concentrations of patients across the AD spectrum by an improved digital enzyme-linked immunosorbent assay (ELISA) technique. Confirms the predictive and diagnostic value of this method for AD patients and study the relationships between these biomarkers and cognitive status. Methods: Plasma concentrations of amyloid-beta 40 (Aß40), amyloid-beta 42 (Aß42) and plasma phosphorylated tau at threonine 181 (p-tau181) were determined in 43 AD patients, 33 mild cognitive impairment (MCI) patients and 40 normal cognition (NC) subjects as healthy controls using the improved digital ELISA technique. In addition, all subjects were required to receive neuropsychological assessments. Results: Plasma p-tau181 level showed certain discrepancies between NC and MCI (p < 0.05), AD (p < 0.01) groups. The level of plasma Aß42 (p < 0.05) and Aß40 (p < 0.01) was significantly different between AD and NC group. The p-tau181 level was able to distinguish AD (AUC = 0.8768) and MCI (AUC = 0.7932) from NC with higher accuracy than Aß42/Aß40 ratio (AUC = 0.8343, AUC = 0.6569). Both p-tau181 (CDR: r = 0.388 p < 0.001; MMSE: r = -0.394 p < 0.001) and Aß42/Aß40 ratio (CDR: r = -0.413 p < 0.001; MMSE: r = 0.358 p < 0.001) showed stronger positive correlation with clinical dementia rating (CDR) and mini mental state examination (MMSE) scores than Aß42 (CDR: r = -0.280 p = 0.003; MMSE: r = 0.266 p = 0.005) or Aß40 (CDR: r = 0.373 p < 0.001; MMSE: r = -0.288 p = 0.002) alone. Conclusion: Plasma p-tau181 level and Aß42/Aß40 ratio showed promising values in diagnosis of AD and MCI. Our results indicate that this improved digital ELISA diagnosis approach can facilitate early recognition and management of AD and pre-AD patients.

Vitamin D deficiency and the risk of diabetic retinopathy in patients with type 2 diabetes in Tibet: a cross-sectional analysis.

BACKGROUND: Diabetic retinopathy (DR) is one of the most common complications of diabetes worldwide. The aim of this study was to assess the prevalence of DR in hospitalized patients with type 2 diabetes (T2DM) in Tibet and to identify risk factors that may influence the occurrence of DR. METHODS: This was a cross-sectional study conducted in a third-class hospital in the Tibet Autonomous Region. The prevalence of DR in hospitalized patients with T2DM was measured. Univariate and multivariate logistic regression, restricted cubic spline (RCS) analysis and receiver-operating characteristic curve analysis were used to investigate the risk factors for DR. RESULTS: The prevalence of DR was 29.3%. The duration of diabetes; concentrations of 25-OH-VitD3, hemoglobin, fasting insulin, alanine aminotransferase, total bilirubin, and creatinine; and HOMA-IR were significantly different between DR patients and non-DR patients (all P < 0.05). Univariate and multivariate logistic regression revealed that a longer duration of diabetes and lower 25-OH-VitD3 levels were associated with increased DR risk. RCS analysis suggested overall positive associations of the duration of diabetes and 25-OH-VitD3 concentrations with DR risk (P nonlinearity < 0.05). The turning points for the duration of diabetes and 25-OH-VitD3 concentrations were 5.1 years and 10.6 ng/mL, respectively. The sensitivity, specificity, and area under the receiver-operating characteristic curve for the combination of the duration of diabetes and 25-OH-VitD3 levels were 79.4%, 69.4% and 0.764, respectively. CONCLUSIONS: Given the high prevalence of DR in hospitalized patients with T2DM in Tibet, vitamin D supplementation seems to be important in the prevention of DR to some degree.

Corrigendum: Blood glucose to predict symptomatic intracranial hemorrhage after endovascular treatment of acute ischemic stroke with large infarct core: a prospective observational study.

[This corrects the article DOI: 10.3389/fneur.2024.1367177.].

Naringenin enhances the efficacy of ferroptosis inducers by attenuating aerobic glycolysis by activating the AMPK-PGC1α signalling axis in liver cancer.

Liver cancer is a heterogeneous disease characterized by poor responses to standard therapies and therefore unfavourable clinical outcomes. Understanding the characteristics of liver cancer and developing novel therapeutic strategies are imperative. Ferroptosis, a type of programmed cell death induced by lipid peroxidation, has emerged as a potential target for treatment. Naringenin, a natural compound that modulates lipid metabolism by targeting AMPK, shows promise in enhancing the efficacy of ferroptosis inducers. In this study, we utilized liver cancer cell lines and xenograft mice to explore the synergistic effects of naringenin in combination with ferroptosis inducers, examining both phenotypic outcomes and molecular mechanisms. Our study results indicate that the use of naringenin at non-toxic doses to hepatocytes can significantly enhance the anticancer effects of ferroptosis inducers (erastin, RSL3, and sorafenib). The combination index method confirmed a synergistic effect between naringenin and ferroptosis inducers. In comparison to naringenin or ferroptosis inducers alone, the combined therapy caused more robust lipid peroxidation and hence more severe ferroptotic damage to cancer cells. The inhibition of aerobic glycolysis mediated by the AMPK-PGC1α signalling axis is the key to naringenin's effect on reducing ferroptosis resistance in liver cancer, and the synergistic cytotoxic effect of naringenin and ferroptosis inducers on cancer cells was reversed after pretreatment with an AMPK inhibitor or a PGC1α inhibitor. Taken together, these findings suggest that naringenin could boost cancer cell sensitivity to ferroptosis inducers, which has potential clinical translational value.

Ebselen improves lipid metabolism by activating PI3K/Akt and inhibiting TLR4/JNK signaling pathway to alleviate nonalcoholic fatty liver.

Nonalcoholic fatty liver disease (NAFLD), a metabolic disease associated with obesity and type 2 diabetes. Due to its complex pathogenesis, there are still limitations in the knowledge of the disease. To date, no drug has been approved to treat NAFLD. This study aims to explore the role and mechanism of Ebselen (EbSe) in NAFLD. A high-fat diet-induced mouse model of NAFLD was employed to investigate EbSe function in NAFLD mice by EbSe gavage and to regularly monitor the mouse body weight. HE and oil red O staining were performed, respectively, to detect the pathological damage and lipid accumulation in mouse liver tissues. The biochemical and ELISA kits were employed to measure the levels of ALT, AST, TG, TC, LDL-C, HDL-C and pro-inflammatory cytokines within mouse serum or liver tissue. The expression of key proteins of PPARα, fatty acid ß oxidation-related protein, PI3K/Akt and TLR4/JNK signaling pathway was detected by western blot. EbSe significantly downregulated body weight, liver weight and liver lipid accumulation in NAFLD mice and downregulated ALT, AST, TG, TC, LDL-C and increased HDL-C serum levels. EbSe upregulated the expression levels of PPARα and fatty acid ß oxidation-associated proteins CPT1α, ACOX1, UCP2 and PGC1α. EbSe promoted Akt and PI3K phosphorylation, and inhibited TLR4 expression and JNK phosphorylation. EbSe can upregulate PPARα to promote fatty acid ß-oxidation and improve hepatic lipid metabolism. Meanwhile, EbSe also activated PI3K/Akt and inhibited TLR4/JNK signaling pathway. EbSe is predicted to be an effective therapeutic drug for treating NAFLD.

Study on correlation between perioperative cognitive function and nutritional status in elderly patients with gastric cancer.

OBJECTIVE: To investigate the cognitive function and nutritional status of elderly patients with gastric cancer during perioperative period, and to analyze their correlation. METHODS: Aged patients undergoing gastric cancer surgery in The Affiliated Cancer Hospital of Shandong First Medical University from March to October 2021 were selected as the subjects of this study. The monitoring data of cognitive function and nutritional status were retrospectively analyzed from 1 to 3 days before surgery, 1 and 3 days after surgery, 7 days after surgery (before discharge) and 30 days after surgery to analyze the correlation between cognitive function and nutritional status in elderly patients with gastric cancer. RESULTS: the incidence of mild cognitive impairment in elderly patients with gastric cancer was 52.43 %, the visual space of the two groups' (mild cognitive impairment) ability of execution, name, attention, language, abstract thinking, delayed memory and cognitive function scores were lower than 1 set of directional force (cognitive function in normal group), statistically significant difference (P < 0.05). The nutritional status of elderly patients with gastric cancer was lower than that of healthy elderly group at the same period (P < 0.05). The scores of visual spatial executive function, name, attention, delayed memory, orientation and total score of cognitive function in elderly gastric cancer patients were positively correlated with nutritional status (P < 0.05). CONCLUSIONS: The cognitive function and nutritional status of elderly patients with gastric cancer are both in a low state during treatment and a higher level of cognitive function can help patients maintain a more correct nutritional cognition, and the nutritional status of patients will be relatively better. There is a positive correlation between cognitive function and nutritional status in elderly patients with gastric cancer, which should be paid attention to in the treatment.

Blood glucose to predict symptomatic intracranial hemorrhage after endovascular treatment of acute ischemic stroke with large infarct core: a prospective observational study.

Introduction: Symptomatic intracranial hemorrhage (sICH) is a serious complication of acute ischemic stroke (AIS) after endovascular treatment (EVT). Limited data exist regarding predictors and clinical implications of sICH after EVT, underscoring the significance of identifying risk factors to enhance prevention strategies. Therefore, the main objective of this study was to evaluate the incidence of sICH and identify its predictors after EVT in patients with large infarct core-AIS in the pre-circulation stage. Methods: Using data from the EVT for the Pre-circulation Large Infarct Core-AIS Study, we enrolled patients who were treated with EVT from the Prospective Multicenter Cohort Study of Early Treatment in Acute Stroke (MAGIC) registry. Baseline demographics, medical history, vascular risk factors, blood pressure, stroke severity, radiographic features, and EVT details were collected. The patients were classified into three groups: without intracranial hemorrhage (ICH), with asymptomatic intracranial hemorrhage (aICH), and sICH, based upon the occurrence of sICH. The main outcomes were the occurrence of sICH according to the Heidelberg Bleeding Classification and functional condition at 90 days. Multivariate logistic regression analysis and receiver operating characteristic (ROC) curves were used to identify independent predictors of sICH after EVT. Results: The study recruited a total of 490 patients, of whom 13.3% (n = 65) developed sICH. Patients with sICH had less favorable outcomes than those without intracranial hemorrhage (ICH) and those with aICH (13.8% vs. 43.5% vs. 32.2%, respectively; p < 0.001). The overall mortality was 41.8% (n = 205) at 90 days post-EVT. The univariate analysis revealed significant differences among the three groups in terms of blood glucose levels at admission, probability of favorable outcomes, incidence of brain herniation, and 90-day mortality. The multifactorial logistic regression analysis revealed that the blood glucose level at admission [odds ratio (OR) 1.169, p < 0.001, confidence interval (CI) 1.076-1.269] was an independent predictor of sICH. A blood glucose level of 6.95 mmol/L at admission was the best predictor of sICH, with an area under the ROC curve (AUC) of 0.685 (95% CI: 0.616-0.754). Discussion: The study findings demonstrated that the probability of sICH after EVT was 13.3% in patients with pre-circulation large infarct core-AIS, and sICH increased the risk of an unfavorable prognosis. Higher blood glucose levels at admission were associated with sICH after EVT in patients with pre-circulation large infarct core AIS. These findings underscore the importance of early management strategies to mitigate this risk.

Dynamic Marine Atmospheric Corrosion Behavior of AZ91 Mg Alloy Sailing from Yellow Sea to Western Pacific Ocean.

In this work, the dynamic marine atmospheric corrosion behavior of AZ91 Mg alloy sailing from Yellow Sea to Western Pacific Ocean was studied. The corrosion rates were measured using the weight loss method. The microstructure, phase, and chemical composition of corroded samples were investigated by SEM, EDS, XRD, and XPS. The results show that the evolution of corrosion rates of AZ91 Mg alloy was divided into three stages: rapidly increasing during the first 3 months, then remaining stable for the next three months, and finally decreasing after 6 months. The annual corrosion rate of Mg alloy reached 32.50 µm/y after exposure for 12 months in a dynamic marine atmospheric environment, which was several times higher than that of the static field exposure tests. AZ91 magnesium alloy was mainly subjected to localized corrosion with more destructiveness to Mg parts, which is mainly due to the synergistic effect of high relative humidity, the high deposition rate of chloride ion, sulfur dioxide acidic gas produced by fuel combustion, and rapid temperature changes caused by the alternating changes in longitude and latitude during navigation. As the exposure time increased, the corrosion pits gradually increased and deepened. The maximum depth of the corrosion pit was 197 µm after 12 months of exposure, which is almost 6 times the average corrosion depth. This study provides scientific data support for the application of magnesium alloys in shipborne aircraft and electronic equipment. The results could provide guidance for the design of new magnesium alloys and development of anti-corrosion technologies.

Swing Origami-Structure-Based Triboelectric Nanogenerator for Harvesting Blue Energy toward Marine Environmental Applications.

The appearance of triboelectric nanogenerators (TENG) provides a promising energy technology for harvesting abundant water wave energy. Here, the design and fabrication of a swinging origami-structured TENG (SO-TENG) tailored specifically for water wave energy harvesting are presented. The design incorporates an oscillating structure weighted at the bottom, inducing reciprocating motion propelled by the inertia of passing water waves. This reciprocating motion efficiently converts mechanical into electrical energy through the origami structure. By employing origami as the monomer structure, the surface contact area between friction layers is enhanced, thereby optimizing output performance. the swinging structure, combined with the placement of heavy objects, enhances the folding and contact of the origami, allowing it to operate effectively in low-frequency water wave environments. This configuration exhibits robust power generation capabilities, making it suitable for powering small electronic devices in water wave environments. Furthermore, when applied to metal corrosion protection, the SO-TENG demonstrates notable efficacy. Compared to exposed Q235 carbon steel, Q235 carbon steel protected by SO-TENG exhibits a significant reduction in open-circuit potential drop, approximately 155 mV, indicative of superior anti-corrosion properties. It lays a solid foundation for water wave energy collection and self-powered metal corrosion protection in marine environments.

Identification of a novel LFNG variant in a Chinese fetus with spondylocostal dysostosis and a systematic review.

Spondylocostal dysostosis (SCDO) encompasses a group of skeletal disorders characterized by multiple segmentation defects in the vertebrae and ribs. SCDO has a complex genetic etiology. This study aimed to analyze and identify pathogenic variants in a fetus with SCDO. Copy number variant sequencing and whole exome sequencing were performed on a Chinese fetus with SCDO, followed by bioinformatics analyses, in vitro functional assays and a systematic review on the reported SCDO cases with LFNG pathogenic variants. Ultrasound examinations in utero exhibited that the fetus had vertebral malformation, scoliosis and tethered cord, but rib malformation was not evident. We found a novel homozygous variant (c.1078 C > T, p.R360C) within the last exon of LFNG. The variant was predicted to cause loss of function of LFNG by in silico prediction tools, which was confirmed by an in vitro assay of LFNG enzyme activity. The systematic review listed a total of 20 variants of LFNG in SCDO. The mutational spectrum spans across all exons of LFNG except the last one. This study reported the first Chinese case of LFNG-related SCDO, revealing the prenatal phenotypes and expanding the mutational spectrum of the disorder.

Predictors for unfavorable prognosis after stroke with perforator artery disease.

Background and purpose: Perforator artery disease (PAD) is an important subtype of ischemic stroke. The risk factors affecting the prognosis of patients with PAD are unclear. This study aimed to investigate the risk factors affecting the unfavorable prognosis of PAD. Methods: Patients with PAD were enrolled from Dushu Lake Hospital Affiliated to Soochow University and diagnosed as stroke with PAD during the period from September 2021 to July 2023 and followed up with a modified Rankin Scale (mRS) after 90 days, defining the mRS of 0-2 as a group with favorable prognosis, and 3-6 as a group with unfavorable functional outcome. Logistic regression was used to identify predictors for PAD. Multiple logistic regression analysis and receiver operating characteristics (ROC) were used to identify predictors of unfavorable prognosis. Results: Of the 181 enrolled patients, 48 (26.5%) were identified with unfavorable prognosis. On multivariate analysis, increased age (OR = 1.076, 95% CI: 1.012 ~ 1.144, p = 0.019), higher National Institutes of Health Stroke Scale (NIHSS) score at admission (OR = 2.930, 95% CI: 1. 905 ~ 4.508, p < 0.001), and increased neutrophil-to-lymphocyte ratio (NLR) (OR = 3.028, 95% CI: 1.615 ~ 5.675, p = 0.001) were independent risk factors for unfavorable prognosis in patients with PAD, and the area under the receiver operating characteristic curve was 0.590, 0.905, and 0.798, and the multi-factor diagnostic model (Model 2) showed reliable diagnostic specificity and sensitivity (area under the curve = 0.956, p < 0.001, specificity 0.805, sensitivity 0.958, accuracy 0.845). Conclusion: Increased baseline NLR and NIHSS score and aging may be independent risk factors for unfavorable prognosis of patients with PAD. NLR can be used as a potential biological indicator to predict the prognosis of stroke with PAD.

Progress in the research of immunotherapy­related hyperprogression (Review).

Immunotherapy has become an effective method for the treatment of a variety of malignant tumors. However, with the development of immunotherapy, the phenomenon of hyperprogression in patients with cancer has gradually attracted attention. Hyperprogression refers to a condition in which the progression of a disease during treatment of a patient with cancer is suddenly accelerated. To date, no reliable marker has been found to predict accelerated tumor growth during immune checkpoint inhibitor (ICI) treatment. The aim the present study was to summarize the definition of hyperprogression and the difference between hyperprogression and pseudocytosis, and investigate the potential mechanisms of hyperprogression including clinical characteristics, potential molecular markers and the immune microenvironment. The effect of macrophage-related different types and factors on tumors in the immune microenvironment was analyzed, and the findings may be used to determine the future directions of research in hyperprogression.

YTHDF2-regulated matrilin-3 mitigates post-reperfusion hemorrhagic transformation in ischemic stroke via the PI3K/AKT pathway.

Hemorrhagic transformation can complicate ischemic strokes after recanalization treatment within a time window that requires early intervention. To determine potential therapeutic effects of matrilin-3, rat cerebral ischemia-reperfusion was produced using transient middle cerebral artery occlusion (tMCAO); intracranial hemorrhage and infarct volumes were assayed through hemoglobin determination and 2,3,5-triphenyltetrazoliumchloride (TTC) staining, respectively. Oxygen-glucose deprivation (OGD) modeling of ischemia was performed on C8-D1A cells. Interactions between matrilin-3 and YTH N6-methyladenosine RNA binding protein F2 (YTHDF2) were determined using RNA immunoprecipitation assay and actinomycin D treatment. Reperfusion after tMCAO modeling increased hemorrhage, hemoglobin content, and infarct volumes; these were alleviated by matrilin treatment. Matrilin-3 was expressed at low levels and YTHDF2 was expressed at high levels in ischemic brains. In OGD-induced cells, matrilin-3 was negatively regulated by YTHDF2. Matrilin-3 overexpression downregulated p-PI3K/PI3K, p-AKT/AKT, ZO-1, VE-cadherin and occludin, and upregulated p-JNK/JNK in ischemic rat brains; these effects were reversed by LY294002 (a PI3K inhibitor). YTHDF2 knockdown inactivated the PI3K/AKT pathway, inhibited inflammation and decreased blood-brain barrier-related protein levels in cells; these effects were reversed by matrilin-3 deficiency. These results indicate that YTHDF2-regulated matrilin-3 protected ischemic rats against post-reperfusion hemorrhagic transformation via the PI3K/AKT pathway and that matrilin may have therapeutic potential in ischemic stroke.

Highly porous and rough polydimethylsiloxane film-based triboelectric nanogenerators and its application for electrochemical cathodic protection.

The development and utilization of triboelectric nanogenerator (TENG) are very important for realizing energy cleaning in electrochemical processes. However, limited electrical output performance plays a major stumbling block to this process. Herein, a porous and high-roughness PDMS (PR/PDMS) negative friction layer was obtained by doping PDMS with powdered chitosan and casting using a sacrificial anodic alumina template. A TENG was fabricated by the PR/PDMS with Al film (PR-TENG). The PR-TENG exhibited much better performance than the pure PDMS-based TENG, which was attributed to the porous properties of the PR/PDMS. Under the driving of external mechanical force at 5 Hz, the PR-TENG showed a maximum output open-circuit voltage (Voc) and short-circuit current density (Jsc) of 77.1 V and 33.9 mA/m2, respectively. To prove the concept, the electrochemical cathodic protection system with PR-TENG was constructed. Ultimately, the application prospects of the PR-TENG as a clean energy source for electrochemical processes were explored and evaluated.

Clinical characteristics and the prognosis of diabetic foot in Tibet: A single center, retrospective study.

The objective of this study was to explore the clinical characteristics and prognosis of diabetic foot in hospitalized patients with diabetes in Tibet. To achieve that, patients hospitalized in People's Hospital of Tibet Autonomous Region and diagnosed with diabetic foot ulcer (DFU) from January 1, 2016 to December 31, 2020 were enrolled in the study, and DFU cases of Peking University First Hospital were collected as control group. Analysis and comparison of clinical characteristics of DFU in plateau and plain areas were conducted. Normal distribution data or non-normal distribution data between groups were analyzed by t-test analysis or the nonparametric Mann-Whitney U test, and categorical variants were compared by Chi-square of Pearson. A total of 54 DFU cases were enrolled in the study in the People's Hospital of Tibet Autonomous Region (Tibet group for short). Males accounted for 83.3% (45 cases) in Tibet group, which was higher than that of Peking University First Hospital (Beijing group for short), which accounted for 67.0%. Compared with the DFU patients in the Beijing group, the Tibet group was younger (58.11 ± 12.25 years vs 64.18 ± 11.37 years, P < 0.05), with a shorter disease duration (7.00 years vs 12.00 years, P < 0.05). In contrast, alcohol consumption was higher in the Tibet group (44.4 vs 27.4%, P < 0.05), and the number of patients with smoking habit was higher in the Beijing group (29.6 vs 43.7%, P < 0.05). The Tibet group had higher HbA1c (10.2 vs 8.7%, P < 0.05) and lower DFU proportion (22.2 vs 44.2%, P < 0.05). There was no statistically significant difference in the proportion of moderate to severe infections between the two groups (58.5 vs 59.6%, P = 0.887). Leukocytes (6.75 × 109/L vs 8.72 × 109/L, P < 0.05) and neutrophils (4.07 × 109/L vs 6.26 × 109/L, P < 0.05) in Tibet group were lower. Although the DFU amputation rate in the Tibet group was lower than that in the Beijing group (9.3 vs 29.8%, P < 0.05), there was no statistically significant difference between the two groups in terms of treatment cost, hospital stay, and mortality. In conclusion, patients with DFU in Tibet had a smaller age, shorter duration of diabetes, and more male predominance. The proportions of gangrene and amputation were lower in Tibet, with gangrene accounting for 80% of all amputees.

Regulating N Species in N-Doped Carbon Electro-Catalysts for High-Efficiency Synthesis of Hydrogen Peroxide in Simulated Seawater.

Electrochemical oxygen reduction reaction (ORR) is an attractive and alternative route for the on-site production of hydrogen peroxide (H2 O2 ). The electrochemical synthesis of H2 O2 in neutral electrolyte is in early studying stage and promising in ocean-energy application. Herein, N-doped carbon materials (N-Cx ) with different N types are prepared through the pyrolysis of zeolitic imidazolate frameworks. The N-Cx catalysts, especially N-C800 , exhibit an attracting 2e- ORR catalytic activity, corresponding to a high H2 O2 selectivity (≈95%) and preferable stability in 0.5 m NaCl solution. Additionally, the N-C800 possesses an attractive H2 O2 production amount up to 631.2 mmol g-1  h-1 and high Faraday efficiency (79.8%) in H-type cell. The remarkable 2e- ORR electrocatalytic performance of N-Cx catalysts is associated with the N species and N content in the materials. Density functional theory calculations suggest carbon atoms adjacent to graphitic N are the main catalytic sites and exhibit a smaller activation energy, which are more responsible than those in pyridinic N and pyrrolic N doped carbon materials. Furthermore, the N-C800 catalyst demonstrates an effective antibacterial performance for marine bacteria in simulated seawater. This work provides a new insight for electro-generation of H2 O2 in neutral electrolyte and triggers a great promise in ocean-energy application.

Loss of TP53 cooperates with c-MET overexpression to drive hepatocarcinogenesis.

Hepatocellular carcinoma (HCC) is a deadly malignancy with high genetic heterogeneity. TP53 mutation and c-MET activation are frequent events in human HCCs. Here, we discovered that the simultaneous mutations in TP53 and activation of c-MET occur in ~20% of human HCCs, and these patients show a poor prognosis. Importantly, we found that concomitant deletion of Trp53 and overexpression of c-MET (c-MET/sgp53) in the mouse liver led to HCC formation in vivo. Consistent with human HCCs, RNAseq showed that c-MET/sgp53 mouse HCCs were characterized by activated c-MET and Ras/MAPK cascades and increased tumor cell proliferation. Subsequently, a stably passaged cell line derived from a c-MET/sgp53 HCC and corresponding subcutaneous xenografts were generated. Also, in silico analysis suggested that the MEK inhibitor trametinib has a higher inhibition score in TP53 null human HCC cell lines, which was validated experimentally. We consistently found that trametinib effectively inhibited the growth of c-MET/sgp53 HCC cells and xenografts, supporting the possible usefulness of this drug for treating human HCCs with TP53-null mutations. Altogether, our study demonstrates that loss of TP53 cooperates with c-MET to drive hepatocarcinogenesis in vivo. The c-MET/sgp53 mouse model and derived HCC cell lines represent novel and useful preclinical tools to study hepatocarcinogenesis in the TP53 null background.

A retrospective analysis of 25 cases of Addison's disease caused by adrenal tuberculosis in Tibet and review of related literature.

Background: To investigate the clinical characteristics of Addison's disease caused by adrenal tuberculosis in Tibet. After the anti-tuberculosis treatment, the clinical features between continuous glucocorticoid therapy and glucocorticoid withdrawal were analyzed. Methods: Clinical data of patients with Addison's disease caused by adrenal tuberculosis diagnosed in The People's Hospital of Tibet Autonomous Region from January 2015 to October 2021 were collected and analyzed. All patients were taking anti-tuberculosis and glucocorticoids replacement therapy, and the root cause of the disease was analyzed following prognosis observations. Results: There were 25 patients (24 Tibetan and 1 Han patient) with Addison's disease caused by adrenal tuberculosis, including 18 males and 7 females. A total of 21 cases were followed up successfully, of which 13 cases discontinued anti-tuberculosis drugs successfully, 6 cases discontinued glucocorticoid therapy among the rest, 6 cases continued anti-tuberculosis + glucocorticoid replacement therapy, and 2 cases died. Conclusion: Early diagnosis and proper anti-tuberculosis treatment can improve the prognosis of patients with adrenal tuberculosis. Moreover, screening and educating Tibetan people regarding the potential risk and adversities of adrenal tuberculosis is crucial for eradicating the disease.

The association between living altitude and serum leptin concentrations in native women.

Background: Lower diabetes prevalence and cardiovascular mortality have been observed in residents at a higher altitude. Leptin is associated with incident diabetes and adverse cardiovascular outcomes, and our aim was to investigate the association of living altitude with serum leptin concentrations. Methods: Two cross-sectional surveys were used in this study, including native populations living at Tibet (high altitude) and Beijing (low altitude). A propensity score was conducted for matching age and body mass index (BMI) between native women at high and low altitude. Pearson's correlation analysis was performed to evaluate the correlation of leptin with other variables. Results: A total of 1414 native women were included in this study, including 594 at high altitude and 820 at low altitude. The serum leptin concentrations of native women living at high altitude were 13.74 ± 11.03 ng/ml, which was significantly lower than that of native women living at low altitude (20.90 ± 12.91 ng/ml). After matching age and BMI, women living at the high altitude still had lower serum leptin concentrations. After adjusting for the potential confounding factors, the correlation coefficient between Ln (leptin) and BMI of women at high altitude was significantly lower than that of women at low altitude (0.228 versus 0.559; P <0.0001). The serum leptin concentrations of each BMI subgroup (<18.5, 18.5 to <25, 25 to <30, ≥ 30 kg/m2) in women at high altitude were lower than that in women at low altitude. Conclusions: Serum leptin concentrations were significantly decreased in native women living at high altitude, and living altitude may alter the correlation of BMI and leptin. The findings of our study support that residents at high altitude have a protective effect with regards to improving cardiovascular and metabolic outcomes.